Why We Age: Understanding the Science and Genetics Behind Ageing and Health Span
Introduction | The Science of Ageing and Longevity | What is Ageing? | The Cellular and Molecular Mechanisms of Ageing | The Impact of Inflammation on Ageing | Oxidative Stress | The Roles of Telomeres and Telomerase in Ageing | Cellular Senescence and Its Impacts on Ageing | Hormonal Changes | The Role of Genetics in Longevity | Ageing: More Than Just A Biological Process
Virtually every modern human being desires a longer, healthier life that minimises the symptoms and effects of ageing. While ageing is not a disorder or a disease in itself, it is a primary risk factor for developing a wide range of major diseases, including chronic diseases that negatively impact the quality of life. Moreover, according to the National Institute on Ageing, many of these diseases seem to accelerate the natural process of ageing. This results in declines in physical and cognitive function and an overall reduction in health, wellness, and resilience.
The science behind longevity aims to develop a clear and concise understanding of exactly how the process of ageing takes place in the human body and the key drivers behind this process. These drivers also need to be separated from the basic biologies that drive disease, such as inflammation, which is vital to the healing process. However, chronic inflammation without a clear cause, such as infection, can increase susceptibility to various age-related conditions and accelerate their progression.
The importance of taking control of your health to improve your life and health span cannot be overstated. According to Harvard Health, adopting healthy habits enables people to live significantly longer lives than their counterparts. Research from the Harvard T.H. Chan School of Public Health surveyed data from over 78,000 women and 40,000 men, assessing 34 years’ worth of data for the women and 28 years’ worth of data for the men.
The researchers assessed information on physical activity levels, diets, body weight, alcohol consumption and smoking and discovered that people who enjoyed a healthy lifestyle and diet maintained a healthy weight and did not smoke or drink excessively lived longer lives. On average, the healthier women lived 14 years longer, and the men lived 12 years longer. People who adopted no healthy habits were significantly more likely to suffer premature deaths from cardiovascular disease or cancer.
It is also important to note that life span is not the sole indicator of wellness into one’s senior years. Life span refers to the estimated number of years that an individual will live. ‘Health span’ is the number of years in which a person is expected to live in good health without experiencing chronic illness, disability, cognitive decline, and disease.
While advances in modern healthcare have been able to improve both life span and health span, the onset of chronic diseases later in life is still a notable factor affecting both public and individual health outcomes.
In this article, we will explore the science and genetics behind ageing and health span. Plus, we’ll provide recommendations for optimising your health and protecting it as the natural ageing process takes place.
The Science of Ageing and Longevity
What is Ageing?
Ageing is a natural biological process resulting from accumulating a range of cellular and molecular damages within the body. This accumulation leads to a gradual decline in mental and physical ability, a heightened risk of disease, and death.
These changes do not progress in a linear way and can take place at any age. There is a notable range of health outcomes for people in older age. Ageing is often linked to lifestyle and environmental factors as well, including traumatic events, stress, and major life transitions.
The Cellular and Molecular Mechanisms of Ageing
The process of ageing can be described as a state of progressing decline paired with an increase in mortality risk. On a cellular and molecular level, ageing is the accumulation of cellular damage, including DNA mutations, lesions, misfolded proteins, and impaired function of the cells, organelles, and mitochondria.
These alterations lead to the development and accumulation of dysfunctional cells, which hinder the processes involved with homeostasis. This, in turn, reduces the body’s potential to regenerate, causing chronic and low-grade inflammation and impairing intercellular communications. This molecular damage, combined with epigenetic modifications, gene expression dysregulation, and impaired endocrine signalling and communication, drives the process of ageing and highlight this process as a primary risk factor for age-related disease and mortality.
The Impact of Inflammation on Ageing
A growing body of research suggests that molecular inflammation plays a primary role in driving the ageing process and the development of age-related conditions and diseases. ‘Inflamm-aging’ is the term used to describe low-grade, chronic, systemic inflammation in the context of ageing, which takes place in the absence of diagnosable infection.
Chronic inflammation often stems from damaged cells and macromolecules due to an increase in their production or hindered elimination. The gut’s ability to sequester and eliminate pathogens also declines with age. This allows a number of harmful by-products generated from microbiota populations to permeate the tissues surrounding them and further exacerbate inflammation.
Low-grade, persistent inflammation is a common feature of ageing, and has been linked to a variety of age-related diseases, including type II diabetes, cardiovascular disease, cancers, and neurodegenerative disorders.
It can be triggered by a wide range of factors, including unhealthy lifestyle choices such as alcohol consumption, processed food and refined sugar consumption, a sedentary lifestyle, and smoking.
Free radicals and reactive oxygen species (ROS) are continually produced by virtually all living tissues. These compounds have the potential to damage lipids, proteins and DNA, especially when ROS are present in high concentrations. This elevated ROS concentration leads to a condition known as oxidative stress, which also plays a key role in the acceleration of ageing.
Reactive oxygen species cause structural damage to cells and tissues and act as significant mediators in various biological signalling processes. Elevated ROS levels in the body can cause a dysregulation of redox-sensitive signalling pathways, most notably intracellular glutathione redox status (REDST), which causes cellular dysfunction. Research shows that oxidative changes in human plasma and REDST are associated with age-related disease progression.
The Roles of Telomeres and Telomerase in Ageing
The tips of all eukaryotic chromosomes feature specialised DNA bundles known as telomeres, which consist of thousands of repeated DNA sequences that vary between organisms. In humans and mammals, the sequence is 5′-TTAGGG-3′. These telomeres are protected from cellular DNA repair mechanisms as they have single-strand overhangs which resemble damaged DNA. In humans and some other species, these overhangs bind to complementary DNA repetitions in our double-strand DNA, prompting the ends of telomeres to form ‘protecting loops’. The proteins associated with the ends of telomeres are also designed to protect them and prevent them from initiating DNA repair pathways.
The repeats which constitute telomeres are slowly eroded over continuous division cycles, offering a buffer that safeguards internal chromosome regions which bear genes. The shortening of telomeres has been linked to cellular ageing, and their loss could help to explain why cells can only divide a certain number of times.
Some cells can reverse the shortening of their telomeres by expressing the enzyme telomerase, which extends the telomeres of chromosomes. Telomerase is classified as an RNA-dependent DNA polymerase, which is an enzyme that can create DNA using RNA. This enzyme binds to RNA molecules containing sequences that complement the telomeric repeats. It extends the overhanging telomere DNA using RNA as a type of template, and when the overhang is at sufficient length, the DNA replication system can create a matching strand, thereby producing double-strand DNA. This process lengthens telomeres, helping to reduce the risk and progression of diseases related to telomere shortening, including cancer.
An epigenetic clock such as Horvath’s Clock is used to measure the biological age of cells. This test measures the accumulation of methyl groups in an individual’s DNA molecules and is based on the epigenetic clock theory of ageing developed and extended by Horvath and Raj in 2010. Horvath suggested that biological ageing is an unintentional consequence of both development and maintenance programs, the “molecular footprints” which create DNA methylation age estimators.
He also postulated that the exact mechanisms that link the molecular processes to declines in tissue function are both likely related to intracellular changes and adjustments in cell compositions. At a molecular level, this theory suggests that DNAm age is an approximate estimation of a group of innate ageing processes that interlink with other core causes of ageing to accelerate a loss of tissue function.
Cellular Senescence and Its Impacts on Ageing
Cellular senescence is the process through which cells stop multiplying. However, these cells do not die when they technically should. Instead, they remain in place and release compounds that trigger chronic inflammation. This action can persist over time and spread inflammation throughout the body, damaging nearby cells in the process.
Research shows that the compounds and molecules expressed by senescent cells play critical roles throughout human lifespans and in wound healing, childbirth, and the development of embryos.
The number of senescent cells present in the body rises with age. As the immune system becomes less effective with age too, these senescent cells accumulate. When they do, they can hinder the body’s ability to withstand illness and stress, heal from injury, and maintain healthy cognitive function.
Cellular senescence has been linked to a variety of age-related conditions, including cardiovascular disease, cancer, diabetes, Alzheimer’s disease, dementia, osteoporosis, and osteoarthritis. It is also connected to declines in mobility, cognitive performance, and eyesight, according to the National Institute on Aging.
Age-related hormonal imbalance can contribute to declines in physiological function, including cognitive function, metabolism, and body composition. For instance, a decrease in growth hormone production can lead to reduced muscle mass, an increase in fat accumulation, and a loss of cognitive function over time.
The Role of Genetics in Longevity
The study of the role of genes in longevity is still a developing science. Currently, it is estimated that around one quarter of the variation in human life spans is determined by genes, including APOE, FOXO3, and CETP. Not all of these genes are found in individuals with notably long life spans, but it has been theorised that variants in a range of genes – both identified and unidentified – work in synergy to promote both a long life span and a longer health span.
Some of the key genes that affect longevity in humans include:
- SIRT1: The SIRT1 gene encodes the sirtuin 1 protein.
- SIRT3: The SIRT3 gene encodes the sirtuin 3 protein.
- SIRT6: The SIRT6 gene encodes the sirtuin 6 protein.
- FOXO3: The FOXO3 gene encodes the forkhead box O3 protein.
- AMPK: AMP-activated protein kinase (AMPK).
AMPK is a type of protein that works together with three key molecules; the catalytic alpha subunit and two assistants called regulatory gamma and beta subunits. The catalytic alpha subunit leads the process, and the regulatory subunits help to ensure that the process is carried out optimally. The genes PRKAA1 and PRKAA2 create the catalytic subunit. The genes PRKAB1, PRKAB2, PRKAG1, PRKAG2, and PRKAG3 create the regulatory subunits. AMPK maintains homeostasis, regulates cellular energy usage, decreases inflammation, supports metabolic pathways and processes, and promotes autophagy and healthier ageing.
The mTOR gene, or mechanistic target of rapamycin, is another important factor in ageing. Research highlights mTOR as a crucial regulator of ageing and life span, as it supports cellular metabolism and integrates nutrient sensing with cellular processes responsible for cell development and proliferation. MTOR features in a variety of important cellular processes as they pertain to ageing, including nutrient sensing, autophagy, mitochondrial function and dysfunction, cellular senescence, and stem cell functioning.
Nicotinamide adenine dinucleotide or NAD+ is a coenzyme and is thus not encoded by any specific genes. However, there are certain genes involved in its synthesis, including NAMPT (nicotinamide phosphoribosyltransferase), which is a rate-limiting enzyme in the NAD+ salvage pathway. NAD+ levels decline naturally with age, and this decline has been linked to a range of age-associated diseases, including cancer, metabolic disease, sarcopenia, and cognitive decline.
Research suggests that many of these diseases can be slowed or reversed by restoring NAD+ levels in the body, thus extending the human life span and health span in tandem.
Ageing: More Than Just A Biological Process
The process of ageing is a complex series of biological interactions between cells, molecules, proteins, enzymes, genes, and external factors such as environment and lifestyle. While the rate at which we age is coded, at least to a degree, in our genetic makeup, environmental factors still play a critical role in developing or suppressing age-related conditions and diseases.
Ultimately, adhering to a healthy diet and lifestyle, prioritising physical activity, and limiting inflammation-causing behaviours such as alcohol consumption and smoking can slow the natural ageing process, while certain interventions such as NAD+ supplementation can improve health span and quality of life even further.